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Elevated plus maze
The elevated plus maze (EPM) is a rodent model of anxiety that is used as a screening test for putative anxiolytic compounds and as a general research tool in neurobiological anxiety research. The test setting consists of a plus-shaped apparatus with two open and two enclosed arms, each with an open roof, elevated 40–70 cm from the floor. The model is based on rodents' aversion of open spaces. This aversion leads to the behavior termed thigmotaxis, which involves avoidance of open areas by confining movements to enclosed spaces or to the edges of a bounded space. In EPM this translates into a restriction of movement to the enclosed arms Pellow S, Chopin P, File SE, Briley M. Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 1985;14:149–67.Treit D, Menard J, Royan C. Anxiogenic stimuli in the elevated plus-maze. Pharmacol Biochem Behav 1993;44:463–9. Rodgers RJ. Animal models of anxiety: where next? Behav Pharmacol 1997;8:477–96. Carobrez AP, Bertoglio LJ. Ethological and temporal analyses of anxiety-like behavior: the elevated plus-maze model 20 years on. Neurosci Biobehav Rev 2005;29:1193–205. ). Anxiety reduction in the plus-maze is indicated by an increase in the proportion of time spent in the open arms (time in open arms/total time in open or closed arms), and an increase in the proportion of entries into the open arms (entries into open arms/total entries into open or closed arms). Total number of arm entries and number of closed-arm entries are usually employed as measures of general activity (see Hogg S. A review of the validity and variability of the elevated plus-maze as an animal model of anxiety. Pharmacol Biochem Behav 1996;54:21–30.. While EPM is the most commonly employed behavioral animal anxiety model, there are several issues concerning the validity of the model. Classical clinical anxiolytics, such as benzodiazepines (e.g., Valium), do reduce measures of anxiety in EPM. However, more novel compounds, such as 5-HT1A agonists (e.g., Buspar) give mixed results. Selective serotonin reuptake inhibitors and tricyclic antidepressants, which are commonly employed in clinical settings to treat anxiety disorders, also do not lead to a stable anxiolytic effect on EPMCarobrez AP, Bertoglio LJ. Ethological and temporal analyses of anxiety-like behavior: the elevated plus-maze model 20 years on. Neurosci Biobehav Rev 2005;29:1193–205. . This raises the possibility that EPM is a suitable model for testing GABA-related compounds, such as benzodiazepines or direct GABAA agonists, but not for other drugs. Despite this, the model is commonly employed for screening putative anxiolytics and for general research into the brain mechanisms of anxietyEngin E, Treit D. The effects of intra-cerebral drug infusions on animals' unconditioned fear reactions: A systematic review. Prog Neuro-Psychopharmacol Biol Psychiatry 2008, doi:10.1016/j.pnpbp.2008.03.020, because of the ease of employment and the vast number of studies already in the literature. Effects of different construction See also *Maze learnng *Mazes References Further reading Books *Doremus, T. L., Varlinskaya, E. I., & Spear, L. P. (2004). Age-related differences in elevated plus maze behavior between adolescent and adult rats. New York, NY: New York Academy of Sciences. *Reibaud, M., & Bohme, G. A. (1993). Evaluation of putative anxiolytics in the elevated plus-maze test. San Diego, CA: Academic Press. Papers *Aguiar, M. S., & Brandao, M. L. (1996). Effects of microinjections of the neuropeptide substance P in the dorsal periaqueductal gray on the behavior of rats in the plus-maze test: Physiology & Behavior Vol 60(4) Oct 1996, 1183-1186. *Albrechet-Souza, L., Oliveira, A. R., De Luca, M. C. Z., Tomazini, F. M., Santos, N. R., & Brandao, M. L. (2005). A comparative study with two types of elevated plus-maze (transparent vs. opaque walls) on the anxiolytic effects of midazolam, one-trial tolerance and fear-induced analgesia: Progress in Neuro-Psychopharmacology & Biological Psychiatry Vol 29(4) May 2005, 571-579. *Andrade, M. M. M., Tome, M. F., Santiago, E. S., Lucia-Santos, A., & de Andrade, T. G. C. S. (2003). Longitudinal study of daily variation of rats' behavior in the elevated plus-maze: Physiology & Behavior Vol 78(1) Jan 2003, 125-133. *Andreatini, R., & Bacellar, L. F. S. (2000). Animal models: Trait or state measure? The test-retest reliability of the elevated plus-maze and behavioral despair: Progress in Neuro-Psychopharmacology & Biological Psychiatry Vol 24(4) May 2000, 549-560. *Anseloni, V. Z., & Brandao, M. L. (1997). Ethopharmacological analysis of behaviour of rats using variations of the elevated plus-maze: Behavioural Pharmacology Vol 8(6-7) Nov 1997, 533-540. *Appenrodt, E., Kroning, G., & Schwarzberg, H. (1999). Increased plasma ACTH in rats exposed to the elevated plus-maze is independent of the pineal gland: Psychoneuroendocrinology Vol 24(8) Nov 1999, 833-838. *Beijamini, V., & Guimaraes, F. S. (2006). Activation of neurons containing the enzyme nitric oxide synthase following exposure to an elevated plus maze: Brain Research Bulletin Vol 69(4) Apr 2006, 347-355. *Bertoglio, L. J., & Carobrez, A. P. (2002). Prior maze experience required to alter midazolam effects in rats submitted to the elevated plus-maze: Pharmacology, Biochemistry and Behavior Vol 72(1-2) May 2002, 449-455. *Bertoglio, L. J., & Carobrez, A. P. (2003). Anxiolytic-like effects of NMDA/glycine-B receptor ligands are abolished during the elevated plus-maze trial 2 in rats: Psychopharmacology Vol 170(4) Dec 2003, 335-342. *Biala, G., & Kruk, M. (2008). Calcium channel antagonists suppress cross-tolerance to the anxiogenic effects of D-amphetamine and nicotine in the mouse elevated plus maze test: Progress in Neuro-Psychopharmacology & Biological Psychiatry Vol 32(1) Jan 2008, 54-61. *Biala, G., & Kruk, M. (2008). Cannabinoid receptor ligands suppress memory-related effects of nicotine in the elevated plus maze test in mice: Behavioural Brain Research Vol 192(2) Oct 2008, 198-202. *Blundell, J., & Adamec, R. (2006). Elevated pCREB in the PAG after exposure to the elevated plus maze in rats previously exposed to a cat: Behavioural Brain Research Vol 175(2) Dec 2006, 285-295. *Borta, A., & Schwarting, R. K. W. (2005). Inhibitory avoidance, pain reactivity, and plus-maze behavior in Wistar rats with high versus low rearing activity: Physiology & Behavior Vol 84(3) Mar 2005, 387-396. *Botelho, S., Estanislau, C., & Morato, S. (2007). Effects of under- and overcrowding on exploratory behavior in the elevated plus-maze: Behavioural Processes Vol 74(3) Mar 2007, 357-362. *Bush, D. E. A., & Vaccarino, F. J. (2007). Individual differences in elevated plus-maze exploration predicted progressive-ratio cocaine self-administration break points in Wistar rats: Psychopharmacology Vol 194(2) Oct 2007, 211-219. *Cao, B. J., & Rodgers, R. J. (1996). Different behavioural profiles of the R(+)- and S(-)-enantiomers of 8-hydroxy-2-(di-n-propylamino)tetralin in the murine elevated plus-maze: Behavioural Pharmacology Vol 7(8) Dec 1996, 810-819. *Cao, B. J., & Rodgers, R. J. (1997). Anxiolytic-like profile of p-MPPI, a novel 5HT-sub(1A ) receptor antagonist, in the murine elevated plus-maze: Psychopharmacology Vol 129(4) Feb 1997, 365-371. *Cao, B. J., & Rodgers, R. J. (1997). Influence of 5-HT-sub(1A ) receptor antagonism on plus-maze behaviour in mice. I. Pindolol enantiomers and pindobind 5-HT-sub(1A): Pharmacology, Biochemistry and Behavior Vol 58(2) Oct 1997, 583-591. *Cao, B. J., & Rodgers, R. J. (1997). Influence of 5-HT-sub(1A ) receptor antagonism on plus-maze behaviour in mice. II. WAY 100635, SDZ 216-525 and NAN-190: Pharmacology, Biochemistry and Behavior Vol 58(2) Oct 1997, 593-603. *Cao, B. J., & Rodgers, R. J. (1998). Comparative effects of novel 5-HT-sub(1A ) receptor ligands, LY293284, LY315712 and LY297996, on plus-maze anxiety in mice: Psychopharmacology Vol 139(3) Oct 1998, 185-194. *Carobrez, A. P., & Bertoglio, L. J. (2005). Ethological and temporal analyses of anxiety-like behavior: The elevated plus-maze model 20 years on: Neuroscience & Biobehavioral Reviews Vol 29(8) Dec 2005, 1193-1205. *Carrasco, M. C., Vicens, P., Vidal, J., & Redolat, R. (2006). Effects of co-administration of bupropion and nicotinic agonists on the elevated plus-maze test in mice: Progress in Neuro-Psychopharmacology & Biological Psychiatry Vol 30(3) May 2006, 455-462. *Carvalho, R. C., Patti, C. C., Takatsu-Colemana, A. L., Kameda, S. R., Souza, C. F., Garcez-do-Carmo, L., et al. (2006). Effects of reserpine on the plus-maze discriminative avoidance task: Dissociation between memory and motor impairments: Brain Research Vol 1122(2) Nov 2006, 179-183. *Chung, B. K., & Yoon, B. S. (1996). Effects of medial and lateral septal lesions on expression of anxiety in an elevated plus-maze in rats: Korean Journal of Biological & Physiological Psychology Vol 8(1) 1996, 39-48. *Clenet, F., Hascoet, M., Fillion, G., Galons, H., & Bourin, M. (2005). Role of GABA-ergic and serotonergic systems in the anxiolytic-like mechanism of action of a 5-HT-moduline antagonist in the mouse elevated plus maze: Behavioural Brain Research Vol 158(2) Mar 2005, 339-348. *Cole, J. C., & Rodgers, R. J. (1993). An ethological analysis of the effects of chlordiazepoxide and bretazenil (Ro 16-6028) in the murine elevated plus-maze: Behavioural Pharmacology Vol 4(6) Dec 1993, 573-580. *Collinson, N., & Dawson, G. R. (1997). On the elevated plus-maze the anxiolytic-like effects of the 5-HT-sub(1a ) agonist, 8-OH-DPAT, but not the anxiogenic-like effects of the 5-HT-sub(1A ) partial agonist, buspirone, are blocked by the 5-HT-sub(1A ) antagonist, WAY 100635: Psychopharmacology Vol 132(1) Jul 1997, 35-43. *Coussons-Read, M. E., & Crnic, L. S. (1996). Behavioral assessment of the Ts65Dn nouse, a model for Down syndrome: Altered behavior in the elevated plus maze and open field: Behavior Genetics Vol 26(1) Jan 1996, 7-13. *Da Cunha, I. C., Jose, R. 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Anxiolytic-like effects of rose oil inhalation on the elevated plus-maze test in rats: Pharmacology, Biochemistry and Behavior Vol 77(2) Feb 2004, 361-364. *De Mello Cruz, A. P., Pinheiro, G., Alves, S. H., Ferreira, G., Mendes, M., Faria, L., et al. (2005). Behavioral effects of systemically administered MK-212 are prevented by ritanserin microinfusion into the basolateral amygdala of rats exposed to the elevated plus-maze: Psychopharmacology Vol 182(3) Nov 2005, 345-354. *De-Mello, N., & Carobrez, A. P. (2002). Elevated T-maze as an animal model of memory: Effects of scopolamine: Behavioural Pharmacology Vol 13(2) Mar 2002, 139-148. *Doremus, T. L., Varlinskaya, E. I., & Spear, L. P. (2006). Factor analysis of elevated plus-maze behavior in adolescent and adult rats: Pharmacology, Biochemistry and Behavior Vol 83(4) Apr 2006, 570-577. *Ducottet, C., & Belzung, C. (2004). Behaviour in the elevated plus-maze predicts coping after subchronic mild stress in mice: Physiology & Behavior Vol 81(3) May 2004, 417-426. *Elfline, G. S., Branda, E. M., Babich, M., & Quock, R. M. (2004). Antagonism by NOS inhibition of the behavioral effects of benzodiazepine and GABA-sub(A) receptor agonists in the mouse elevated plus-maze: Neuropsychopharmacology Vol 29(8) Aug 2004, 1419-1425. *Elliott, B. M., Faraday, M. M., Phillips, J. M., & Grunberg, N. E. (2004). Effects of nicotine on elevated plus maze and locomotor activity in male and female adolescent and adult rats: Pharmacology, Biochemistry and Behavior Vol 77(1) Jan 2004, 21-28. *Espejo, E. F. (1997). Effects of weekly or daily exposure to the elevated plus-maze in male mice: Behavioural Brain Research Vol 87(2) Sep 1997, 233-238. *Espejo, E. F. (1997). Structure of the mouse behaviour on the elevated plus-maze test of anxiety: Behavioural Brain Research Vol 86(1) Jun 1997, 105-112. *Estanislau, C., & Morato, S. 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Social interaction and elevated plus-maze tests: Changes in release and uptake of 5-HT and GABA: Neuropharmacology Vol 32(3) Mar 1993, 217-221. *File, S. E., Zangrossi, H., Viana, M., & Graeff, F. G. (1993). Trial 2 in the elevated plus-maze: A different form of fear? : Psychopharmacology Vol 111(4) Jul 1993, 491-494. *Francolin-Silva, A. L., Hernandes, A. d. S., Fukuda, M. T. H., Valadares, C. T., & Almeida, S. S. (2006). Anxiolytic-like effects of short-term postnatal protein malnutrition in the elevated plus-maze test: Behavioural Brain Research Vol 173(2) Sep 2006, 310-314. *Frussa-Filho, R., & de A. Ribeiro, R. (2002). One-trial tolerance to the effects of chlordiazepoxide in the elevated plus-maze is not due to acquisition of a phobic avoidance of open arms during initial exposure: Life Sciences Vol 71(5) Jun 2002, 519-525. *Garcia, A. M. B., Cardenas, F. P., & Morato, S. (2005). Effect of different illumination levels on rat behavior in the elevated plus-maze: Physiology & Behavior Vol 85(3) Jun 2005, 265-270. *Garcia, A. M. B., Martinez, R., Brandao, M. L., & Morato, S. (2005). Effects of apomorphine on rat behavior in the elevated plus-maze: Physiology & Behavior Vol 85(4) Jul 2005, 440-447. *Gonzalez, L. E., & File, S. E. (1997). A five minute experience in the elevated plus-maze alters the state of the benzodiazepine receptor in the dorsal raphe nucleus: Journal of Neuroscience Vol 17(4) Feb 1997, 1505-1511. *Griebel, G., Moreau, J.-L., Jenck, F., Martin, J. R., & et al. (1993). Some critical determinants of the behaviour of rats in the elevated plus-maze: Behavioural Processes Vol 29(1-2) Apr 1993, 37-47. *Griebel, G., Rodgers, R. J., Perrault, G., & Sanger, D. J. (1997). Risk assessment behaviour: Evaluation of utility in the study of 5-HT-related drugs in the rat elevated plus-maze test: Pharmacology, Biochemistry and Behavior Vol 57(4) Aug 1997, 817-827. *Hagenbuch, N., Feldon, J., & Yee, B. K. (2006). Use of the elevated plus-maze test with opaque or transparent walls in the detection of mouse strain differences and the anxiolytic effects of diazepam: Behavioural Pharmacology Vol 17(1) Feb 2006, 31-41. *Hasenohrl, R. U., Nichau, C., Frisch, C., De Souza Silva, M. A., Huston, J. P., Mattern, C. M., et al. (1996). Anxiolytic-like effect of combined extracts of Zingiber officinale and Ginkgo biloba in the elevated plus-maze: Pharmacology, Biochemistry and Behavior Vol 53(2) Feb 1996, 271-275. *Hensler, J. G., Hodge, C. W., & Overstreet, D. H. (2004). Reduced 5-HT-sub-3 receptor binding and lower baseline plus maze anxiety in the alcohol-preferring inbred fawn-hooded rat: Pharmacology, Biochemistry and Behavior Vol 77(2) Feb 2004, 281-289. *Hogg, S. (1996). A review of the validity and variability of the elevated plus-maze as an animal model of anxiety: Pharmacology, Biochemistry and Behavior Vol 54(1) May 1996, 21-30. *Horsley, R. R., Norman, C., & Cassaday, H. J. (2007). Lesions of the nucleus accumbens shell can reduce activity in the elevated plus-maze: Progress in Neuro-Psychopharmacology & Biological Psychiatry Vol 31(4) May 2007, 906-914. *Imhof, J. T., Coelho, Z. M., Schmitt, M. L., Morato, G. S., & et al. (1993). Influence of gender and age on performance of rats in the elevated plus maze apparatus: Behavioural Brain Research Vol 56(2) Sep 1993, 177-180. *Itoh, J., Nabeshima, T., & Kameyama, T. (1990). Utility of an elevated plus-maze for the evaluation of memory in mice: Effects of nootropics, scopolamine and electroconvulsive shock: Psychopharmacology Vol 101(1) May 1990, 27-33. *Izidio, G. S., Spricigo, L., Jr., & Ramos, A. (2005). Genetic differences in the elevated plus-maze persist after first exposure of inbred rats to the test apparatus: Behavioural Processes Vol 68(2) Feb 2005, 129-134. *Jones, N., Duxon, M. S., & King, S. M. (2002). Ethopharmacological analysis of the unstable elevated exposed plus maze, a novel model of extreme anxiety: Predictive validity and sensitivity to anxiogenic agents: Psychopharmacology Vol 161(3) May 2002, 314-323. *Jones, N., King, S. M., & Duxon, M. S. (2002). Further evidence for the predictive validity of the unstable elevated exposed plus-maze, a behavioral model of extreme anxiety in rats: Differential effects of fluoxetine and chlordiazepoxide: Behavioural Pharmacology Vol 13(7) Nov 2002, 525-535. *Jones, N., King, S. M., & Duxon, M. S. (2003). "Further evidence for the predictive validity of the unstable elevated exposed plus-maze, a behavioral model of extreme anxiety in rats: Differential effects of fluoxetine and chlordiazepoxide": Erratum: Behavioural Pharmacology Vol 14(2) Mar 2003, 178. *Kittner, H., Franke, H., Fischer, W., Schultheis, N., Krugel, U., & Illes, P. (2003). Stimulation of P2Y-sub-1 receptors causes anxiolytic-like effects in the rat elevated plus-maze: Implications for the involvement of P2Y-sub-1 receptor-mediated nitric oxide production: Neuropsychopharmacology Vol 28(3) Mar 2003, 435-444. *Koya, E., Spijker, S., Homberg, J. R., Voorn, P., Schoffelmeer, A. N. M., De Vries, T. J., et al. (2005). Molecular reactivity of mesocorticolimbic brain areas of high and low grooming rats after elevated plus maze exposure: Molecular Brain Research Vol 137(1-2) Jun 2005, 184-192. *Lee, C., & Rodgers, R. J. (1991). Effects of benzodiazepine receptor antagonist, flumazenil, on antinociceptive and behavioural responses to the elevated plus-maze in mice: Neuropharmacology Vol 30(12A) Dec 1991, 1263-1267. *Lennartz, R. C. (2008). The role of extramaze cues in spontaneous alternation in plus-maze: Learning & Behavior Vol 36(2) May 2008, 138-144. *Lister, R. G. (1987). The use of a plus-maze to measure anxiety in the mouse: Psychopharmacology Vol 92(2) Jun 1987, 180-185. *Lofgren, M., Johansson, I.-M., Meyerson, B., Lundgren, P., & Backstrom, T. (2006). Progesterone withdrawal effects in the open field test can be predicted by elevated plus maze performance: Hormones and Behavior Vol 50(2) Aug 2006, 208-215. *Martinez, R., Garcia, A. M. B., & Morato, S. (2005). Role of vivarium illumination in rat behavior in the elevated plus-maze: Estudos de Psicologia Vol 10(2) 2005, 239-245. *Martinez, R. C. R., Garcia, A. M. B., Lamprea, M. R., & Morato, S. (2007). Thermal stress decreases general motor activity of rats in the elevated plus-maze but does not alter aversion to the open arms: Behavioural Brain Research Vol 182(1) Aug 2007, 135-139. *Matheus, M. G., & Guimaraes, F. S. (1997). Antagonism of non-NMDA receptors in the dorsal periaqueductal grey induces anxiolytic effect in the elevated plus maze: Psychopharmacology Vol 132(1) Jul 1997, 14-18. *Mechan, A. O., Moran, P. M., Elliot, J. M., Young, A. M. J., Joseph, M. H., & Green, A. R. (2002). A study of the effect of a single neurotoxic dose of 3,4-methylenedioxymethamphetamine (MDMA; "estasy") on the subsequent long-term behaviour of rats in the plus maze and open field: Psychopharmacology Vol 159(2) Jan 2002, 167-175. *Mechan, A. O., Moran, P. M., Elliott, J. M., Young, A. M. J., Joseph, M. H., & Green, A. R. (2002). 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